Sjogren's Syndrome (SS) is an autoimmune disease, characterized as a widespread epitheliitis, which results in dryness of the lining surfaces of the body, producing, most notably, dry mouth and dry eyes. Under this project, the SS Clinic conducts clinical investigation and clinical trials, and collaborates with laboratory investigators in GTTB and Johns Hopkins University in order to elucidate pathogenic mechanisms operative in this disease. During this reporting period, we have demonstrated that elevated IgG levels were predictive of positive labial salivary gland biopsies. Also, we examined the effect of immunomodulatory treatments on the course of the disease. A placebo-controlled, randomized, clinical trial (RCT) of a new biologic agent, etanercept, an inhibitor of tumor necrosis factor alpha, which is found in increased amounts in salivary and lacrimal gland tissues of SS patients, is progressing steadily. Another RCT of dehydroepiandrosterone, based on the hypothesis that sex hormones exert immunomodulatory effects in the disease, has been completed, however this agent had no efficacy. Patients with SS have a much higher risk (~40X) of developing malignant lymphoma than the general population, and we have hypothesized that increased inflammation in salivary tissue, manifesting as higher focus scores, as well as increased serological reactivity and higher immunoglobulin levels, may be risk factors for monoclonal expansion of B cells. This is being examined utilizing a gene rearrangement approach in studies with B cells obtained from the minor salivary glands of SS patients. To potentially facilitate treatment for SS patients, we have asked whether bone marrow progenitor cells, received by transplant patients, are capable of differentiation into both buccal mucosal and salivary epithelial cells (see DE00336). Results thus far with buccal mucosal cells support the hypothesis. Another study is examining whether subsets of SS patients are associated with antibodies specific for distinct autoantigens. Patients with either primary SS or limited scleroderma were found to differ markedly in their pattern of serum anticentromere antibody recognition. In addition, in 15% of SS patients these anticentomere antibodies exclusively recognized CENP-C, and were uniformly associated with antibodies to Ro and La. We have also begun to test the putative role of granzyme B in the generation of neo-autoantigens, and thus in the pathogenesis, of SS.